Blockade of brain alkaline phosphatase efficiently reduces amyloid-β plaque burden and associated cognitive impairment.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Lucia Soria-Tobar, Laura Román-Valero, Álvaro Sebastián-Serrano, Paloma Aivar, Beatriz Álvarez-Castelao, Miguel Díaz-Hernández
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引用次数: 0

Abstract

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient's brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects. These limitations invite us to find alternative strategies for treating patients with AD. Here, we explored whether tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme upregulated in the brain of AD patients and whose inhibition has beneficial effects on tau-induced pathology, is also efficient in reducing senile plaque burden.

Methods: To evaluate whether TNAP may reduce cerebral senile plaque loading and Aβ-related toxicity, we use both pharmacological and genetic approaches. We analyze postmortem samples from human AD patients, APP/PS1 mice (a mouse model that mimics amyloid pathology observed in AD patients) treated or not with TNAP inhibitors, and the newly generated transgenic mouse line, TNAP-deficient APP/PS1 mice.

Results: For the first time, we describe that genetic or pharmacological blockade of TNAP effectively reduces senile plaque burden by promoting its clearance, which leads to amelioration of cognitive impairment caused by Aβ-induced toxicity. These beneficial effects of TNAP inhibition occur concomitantly with higher microglial recruitment toward the senile plaque and increased microglial phagocytic capacity of Aβ by a mechanism involving metalloprotease-depending osteopontin processing. In addition, we also found that TNAP blockade favors LRP1-mediated transport of Aβ through the BBB.

Conclusions: Here, we have shown that TNAP inhibition effectively reduces brain senile plaque burden and associated behavioral defects. Furthermore, given that we had previously reported that TNAP blockade also ameliorates Tau-induced neurotoxicity and increases lifespan of P301S tauopathy mouse model, we can state that TNAP blockade may be a novel and efficient therapy for treating patients with AD.

阻断脑碱性磷酸酶可有效减轻淀粉样蛋白-β斑块的负担和相关认知障碍。
背景:阿尔茨海默病(AD)是最普遍的神经退行性疾病。最近,基于抗淀粉样蛋白-β肽(Aβ)单克隆抗体的三种治疗阿尔茨海默病的新药获得批准,因为它们有助于减轻阿尔茨海默病患者大脑中老年斑的负担。然而,这两种药物的适用性和益处都非常有限,而且还显示出一些副作用。这些局限性促使我们寻找治疗老年痴呆症患者的替代策略。在此,我们探讨了组织非特异性碱性磷酸酶(TNAP)是否也能有效减少老年斑的负担:为了评估 TNAP 是否能减轻大脑老年斑负荷和 Aβ 相关毒性,我们采用了药理学和遗传学方法。我们分析了人类AD患者、APP/PS1小鼠(一种模仿AD患者淀粉样病理的小鼠模型)接受或未接受TNAP抑制剂治疗的尸体样本,以及新产生的转基因小鼠品系--TNAP缺陷APP/PS1小鼠:结果:我们首次描述了基因或药物阻断TNAP可通过促进老年斑块的清除来有效减少老年斑块的负担,从而改善由Aβ诱导的毒性引起的认知障碍。抑制TNAP的这些有益作用是与小胶质细胞向老年斑块的招募增加和小胶质细胞对Aβ的吞噬能力增强同时发生的,其机制涉及依赖金属蛋白酶的骨通素处理。此外,我们还发现阻断 TNAP 可促进 LRP1 介导的 Aβ 通过 BBB 转运:在此,我们证明了 TNAP 抑制能有效减轻脑衰老斑块负担和相关行为缺陷。此外,鉴于我们以前曾报道过阻断 TNAP 还能改善 Tau 诱导的神经毒性并延长 P301S tauopathy 小鼠模型的寿命,我们可以说阻断 TNAP 可能是治疗 AD 患者的一种新型高效疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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